DESCRIPTION (Applicant's Description-edited) One of the most prevalent of cancers, breast cancer, is characterized by hormonal control of its growth. In cell culture, estrogens control the proliferation and differentiation of human breast cancer cells. Recent data from the principal investigator's laboratory demonstrate that the heavy metal, cadmium, mimics the effects of estradiol in human breast cancer cells, in the uterus in organ culture, and in ovariectomized animals, suggesting a role for cadmium in the development of breast cancer. In MCF-7 breast cancer cells, cadmium decreased the steady state level of estrogen receptor, increased the steady state level of progesterone receptor, pS2, and cathepsin D, and induced cell growth. Cadmium also activated a GAL-ER chimeric receptor containing the DNA binding domain of the yeast transcription factor, GAL4, and the hormone binding domain of the estrogen receptor. The results of these studies suggest that the effects of cadmium are mediated through the hormone binding domain of the estrogen receptor independent of estradiol binding. In ovariectomized rats, cadmium had a mitogenic effect on the uterus. In organ culture, cadmium induced two estrogen responsive genes in the mouse uterus suggesting that cadmium also mimics the effects of estradiol on the uterus and the effects are a direct effect. A recent, very large hypothesis-generating case-control study derived from occupational coding of death certificates found an excess risk of breast cancer associated with cadmium exposure. Taken together, these data suggest that environmental exposure to cadmium activates the estrogen receptor and leads to an increased risk of breast cancer. The aims of this grant are three fold: 1) to define the role of cadmium in the development of breast cancer; 2) to determine the mechanism of activation of the estrogen receptor by cadmium; and 3) to determine whether other heavy metals are estrogenic. Aim 1 will test whether cadmium mimics and/or enhances the effects of estradiol in the dimethylbenzanthracene (DMBA)-induced mammary tumor model system. This aim will also test the hypothesis that women exposed to cadmium would benefit from endocrine or other prevention treatment. The studies in aim 2 are designed to determine whether: 1) cadmium activates the estrogen receptor by a direct interaction with the receptor, such as interaction with thiol groups in the hormone binding domain of the receptor or 2) cadmium activates the receptor by an indirect effect, such as activation of signal transduction pathways to influence the phosphorylation of the estrogen receptor. Aim 3 will test whether other candidate heavy metals will activate the estrogen receptor.